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1.
Stem cells, cancer, and cancer stem cells. 总被引:312,自引:0,他引:312
Stem cell biology has come of age. Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine. Perhaps the most important and useful property of stem cells is that of self-renewal. Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells' - rare cells with indefinite potential for self-renewal that drive tumorigenesis. 相似文献
2.
Among the many surprises to arise from studies of prion biology, perhaps the most unexpected is the strain phenomenon whereby a single protein can misfold into structurally distinct, infectious states that cause distinguishable phenotypes. Similarly, proteins can adopt a spectrum of conformations in non-infectious diseases of protein folding; some are toxic and others are well tolerated. However, our understanding of the structural differences underlying prion strains and how these differences alter their physiological impact remains limited. Here we use a combination of solution NMR, amide hydrogen/deuterium (H/D) exchange and mutagenesis to study the structural differences between two strain conformations, termed Sc4 and Sc37 (ref. 5), of the yeast Sup35 prion. We find that these two strains have an overlapping amyloid core spanning most of the Gln/Asn-rich first 40 amino acids that is highly protected from H/D exchange and very sensitive to mutation. These features indicate that the cores are composed of tightly packed beta-sheets possibly resembling 'steric zipper' structures revealed by X-ray crystallography of Sup35-derived peptides. The stable structure is greatly expanded in the Sc37 conformation to encompass the first 70 amino acids, revealing why this strain shows increased fibre stability and decreased ability to undergo chaperone-mediated replication. Our findings establish that prion strains involve large-scale conformational differences and provide a structural basis for understanding a broad range of functional studies, including how conformational changes alter the physiological impact of prion strains. 相似文献
3.
Sung LY Gao S Shen H Yu H Song Y Smith SL Chang CC Inoue K Kuo L Lian J Li A Tian XC Tuck DP Weissman SM Yang X Cheng T 《Nature genetics》2006,38(11):1323-1328
Since the creation of Dolly via somatic cell nuclear transfer (SCNT), more than a dozen species of mammals have been cloned using this technology. One hypothesis for the limited success of cloning via SCNT (1%-5%) is that the clones are likely to be derived from adult stem cells. Support for this hypothesis comes from the findings that the reproductive cloning efficiency for embryonic stem cells is five to ten times higher than that for somatic cells as donors and that cloned pups cannot be produced directly from cloned embryos derived from differentiated B and T cells or neuronal cells. The question remains as to whether SCNT-derived animal clones can be derived from truly differentiated somatic cells. We tested this hypothesis with mouse hematopoietic cells at different differentiation stages: hematopoietic stem cells, progenitor cells and granulocytes. We found that cloning efficiency increases over the differentiation hierarchy, and terminally differentiated postmitotic granulocytes yield cloned pups with the greatest cloning efficiency. 相似文献
4.
An in vivo assay for thymus-homing bone marrow cells 总被引:5,自引:0,他引:5
5.
Under conditions of tissue injury, myocardial replication and regeneration have been reported. A growing number of investigators have implicated adult bone marrow (BM) in this process, suggesting that marrow serves as a reservoir for cardiac precursor cells. It remains unclear which BM cell(s) can contribute to myocardium, and whether they do so by transdifferentiation or cell fusion. Here, we studied the ability of c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic stem cells to regenerate myocardium in an infarct model. Cells were isolated from transgenic mice expressing green fluorescent protein (GFP) and injected directly into ischaemic myocardium of wild-type mice. Abundant GFP+ cells were detected in the myocardium after 10 days, but by 30 days, few cells were detectable. These GFP+ cells did not express cardiac tissue-specific markers, but rather, most of them expressed the haematopoietic marker CD45 and myeloid marker Gr-1. We also studied the role of circulating cells in the repair of ischaemic myocardium using GFP+-GFP- parabiotic mice. Again, we found no evidence of myocardial regeneration from blood-borne partner-derived cells. Our data suggest that even in the microenvironment of the injured heart, c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic stem cells adopt only traditional haematopoietic fates. 相似文献
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7.
The Oort cloud of comets was formed by the ejection of icy planetesimals from the region of giant planets--Jupiter, Saturn, Uranus and Neptune--during their formation. Dynamical simulations have previously shown that comets reach the Oort cloud only after being perturbed into eccentric orbits that result in close encounters with the giant planets, which then eject them to distant orbits about 10(4) to 10(5) AU from the Sun (1 AU is the average Earth-Sun distance). All of the Oort cloud models constructed until now simulate its formation using only gravitational effects; these include the influence of the Sun, the planets and external perturbers such as passing stars and Galactic tides. Here we show that physical collisions between comets and small debris play a fundamental and hitherto unexplored role throughout most of the ejection process. For standard models of the protosolar nebula (starting with a minimum-mass nebula) we find that collisional evolution of comets is so severe that their erosional lifetimes are much shorter than the timescale for dynamical ejection. It therefore appears that collisions will prevent most comets escaping from most locations in the region of the giant planets until the disk mass there declines sufficiently that the dynamical ejection timescale is shorter than the collisional lifetime. One consequence is that the total mass of comets in the Oort cloud may be less than currently believed. 相似文献
8.
Wnt proteins are lipid-modified and can act as stem cell growth factors 总被引:93,自引:0,他引:93
Willert K Brown JD Danenberg E Duncan AW Weissman IL Reya T Yates JR Nusse R 《Nature》2003,423(6938):448-452
Wnt signalling is involved in numerous events in animal development, including the proliferation of stem cells and the specification of the neural crest. Wnt proteins are potentially important reagents in expanding specific cell types, but in contrast to other developmental signalling molecules such as hedgehog proteins and the bone morphogenetic proteins, Wnt proteins have never been isolated in an active form. Although Wnt proteins are secreted from cells, secretion is usually inefficient and previous attempts to characterize Wnt proteins have been hampered by their high degree of insolubility. Here we have isolated active Wnt molecules, including the product of the mouse Wnt3a gene. By mass spectrometry, we found the proteins to be palmitoylated on a conserved cysteine. Enzymatic removal of the palmitate or site-directed and natural mutations of the modified cysteine result in loss of activity, and indicate that the lipid is important for signalling. The purified Wnt3a protein induces self-renewal of haematopoietic stem cells, signifying its potential use in tissue engineering. 相似文献
9.
A clonogenic common myeloid progenitor that gives rise to all myeloid lineages 总被引:153,自引:0,他引:153
Haematopoietic stem cells give rise to progeny that progressively lose self-renewal capacity and become restricted to one lineage. The points at which haematopoietic stem cell-derived progenitors commit to each of the various lineages remain mostly unknown. We have identified a clonogenic common lymphoid progenitor that can differentiate into T, B and natural killer cells but not myeloid cells. Here we report the prospective identification, purification and characterization, using cell-surface markers and flow cytometry, of a complementary clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Common myeloid progenitors give rise to either megakaryocyte/erythrocyte or granulocyte/macrophage progenitors. Purified progenitors were used to provide a first-pass expression profile of various haematopoiesis-related genes. We propose that the common lymphoid progenitor and common myeloid progenitor populations reflect the earliest branch points between the lymphoid and myeloid lineages, and that the commitment of common myeloid progenitors to either the megakaryocyte/erythrocyte or the granulocyte/macrophage lineages are mutually exclusive events. 相似文献
10.
Much of the differentiation of murine T cells takes place in the thymus, perhaps influenced by the operation of stringent selection mechanisms whose existence has been inferred from the high rate of thymocyte turnover in the absence of extensive emigration. The origin of those 1% of total thymocytes which leave the thymus and seed the peripheral lymphoid organs is obscure. Recent thymic emigrants are functionally and phenotypically mature, and the purported greater maturity of medullary relative to cortical thymocytes is often cited a evidence for the medullary origin of thymic emigrants, a suggestion not without its critics. To approach this question, we have now isolated a a subpopulation of thymocytes expressing high levels of a receptor that mediates the homing of blood-borne lymphocytes into peripheral lymph nodes. Surprisingly, this population of cells (1-3% of total thymocytes) is both cortical and immunocompetent, containing approximately half of all thymic cytolytic T-lymphocyte precursors. The combination of homing receptor expression and immunocompetence makes this cortical population ideally suited for emigration to peripheral lymphoid organs. 相似文献